The synthesis of arylamines from amines and aryl halides or halide equivalents such as tosylates and triflates using palladium methodology has enjoyed considerable attention in the literature (Hartwig, J. F. In Modern Amination Methods; Ricci, A., Ed.; Wiley-VCH: Weinheim, Germany, 2000; Wolfe, J. P.; Wagaw, S.; Marcoux, J.-F.; Buchwald, S. L. Acc. Chem. Res. 1998, 31, 805). One reason for this attention is that arylamines possess a diverse range of potential applications in the pharmaceutical, dye, agricultural, and polymer industries. Aryl amines are also useful as ligands for transition metals (Greco, G. E.; Popa, A. I.; Schrock, R. R. Organometallics 1998, 17, 5591).
The chemistry of N-aryl-aza-crown ether derivatives is attracting significant interest because of the utility of these compounds to synthesize fluoroionophores in which, for example, a fluorescent aryl moiety is covalently linked to the nitrogen of an aza-crown ether (Lohr, H.-G.; Vogtle, F. Acc. Chem. Res. 1985, 18, 65; de Silva, et al. Chem. Rev. 1997, 97, 1515). These molecules can serve as sensitive and selective sensors of cations by binding them in the crown ether, thereby modifying the intensity and/or the energy of the signal of the fluorophore. Traditional approaches to the preparation of N-aryl-aza-crown ethers include nucleophilic aromatic substitution of activated aryl halides with aza-crown ethers under high pressure conditions (Matsumoto, et al. J. Chem. Soc., Perkin Trans. I 1995, 2497), or manipulation of functional groups on aniline precursors (Crochet, et al. Chem. Commun. 2000, 289; and Hirano, et al. Angew. Chem., Int. Ed. 2000, 39, 1052). However, these approaches suffer from one or more of the following problems that impede accessibility to this important class of compounds: stringent conditions, multiple step syntheses, low yields, and limited substrate scope.
In recent years, palladium-catalyzed Buchwald-Hartwig amination reactions of aryl halides with amines have emerged as a method of choice for C—N bond forming processes (Muci, A. R.; Buchwald, S. L. Top. Curr. Chem. 2002, 219, 131). In this respect, Witulski et al. have developed a Pd/PPh3 and a Pd/P(o-tol)3 catalyst system for the coupling of aryl and heteroaryl bromides with aza-crown ethers (Witulski, et al. Tetrahedron Lett. 1998, 39, 4807; Witulski, et al. Org. Lett. 2001, 3, 1467). However, this method is limited to electron-poor aryl and heteroaryl bromides. Additionally, the use of P(t-Bu)3, a popular ligand for Pd-catalyzed amination reactions, gave inferior results, probably because of its steric bulk (Hartwig, et al. J. Org. Chem. 1999, 64, 5575; Nishiyama, M.; Yamamoto, T.; Koie, Y. Tetrahedron Lett. 1998, 39, 617).
An improvement to the above protocol was described by Zhang and Buchwald (Zhang, X.-X.; Buchwald, S. L. J. Org. Chem. 2000, 65, 8027) who achieved cross-coupling of aryl bromides with aza-crown ethers using a catalyst system comprising Pd2(dba)3 and biphenyl-based monophosphine ligands with NaO-t-Bu as the base. Although electronically diverse and also ortho-substituted aryl bromides can be employed in these reactions, limitations still exist. For example, the authors noted that poor yields of N-aryl-aza-crown ethers were obtained when weak bases such as Cs2CO3 or K3PO4 were used in place of NaO-t-Bu, thus precluding the introduction of various base-sensitive functional groups into the aryl substrate. Another apparent limitation is that no examples employing aryl chlorides as the coupling partner were reported. Aryl chlorides are cheaper and are available in wider diversity than bromides or iodides, and their applicability in coupling with aza-crown ethers would constitute a significant advance, especially since aza-crown ethers are currently quite expensive.
Thus, ligands described in the literature that effect carbon-nitrogen bond formation often have drawbacks such as high cost, air and moisture instability, inability to effect a variety of transformations, difficulty employing acyclic secondary amines, lack of versatility in the amination reactions of aryl iodides, and requirement for high temperatures to aminate functionalized substrates (for example, substrates possessing ester and nitro functional groups). Despite current interest, there remains a need for novel ligand systems for the formation of carbon-nitrogen bonds.
Furthermore, palladium-catalyzed cross-coupling reactions of aryl halides with arylboronic acids to form biaryls are important transformations. Biaryls are important building blocks in the synthesis of many pharmaceutically active compounds, polymers, herbicides, liquid crystals, and ligands (Miyaura, N.; Suzuki, A. Chem. Rev. 1995, 95, 2458; Stanforth, S. P. Tetrahedron 1998, 54, 263). This cross-coupling reaction is known as the Suzuki-Miyaura reaction and is particularly useful because boron compounds present many advantages in relation to other organometallic compounds such as tin, magnesium, zinc, and silicon: commercial availability, minimal toxicity, and a wide range of functional group compatibility. Moreover, unlike other organometallic compounds, organoboron compounds are air- and moisture-stable reagents. Ancillary ligands on palladium play an important role in the efficiency of this reaction. Among various types of ligands, the most attention has been focused on electron-rich and sterically demanding alkyl phosphines (Little, A. F.; Dai, C.; Fu, G. C. J. Am. Chem. Soc. 2000, 122, 4020). Despite current interest, there remains a need for novel ligand systems for use in the Suzuki-Miyaura reaction.